PROJECT SUMMARY/ABSTRACT There is little doubt that high level Mn exposure can cause neurotoxicity. This competing renewal, however, is focused on the consequences of chronic, low level Mn exposure (i.e., more relevant to occupational and public health). During the current project period, we recruited and studied a cohort of asymptomatic welders with chronic welding exposure at an average level lower than most previous studies. In these welders, we demonstrated that 1) T1 mapping (R1) reflected Mn exposure levels more sensitively than the traditional pallidal index (PI), with Mn accumulation in the brain being highest in basal ganglia (BG) structures, non-linear, and having a specific, marked inflection point in relation to short term exposure metrics; 2) standard neuropsychological tests (NPTs) detected significant welding-related declines in several cognitive function tasks; and 3) R2* [purported measurement for tissue iron (Fe) content] also was higher in BG and correlated significantly with phonemic fluency performance of executive functions. Yet contrary to the original hypothesis based on the work of others, and the fact that the BG both are critical for the motor system and have the highest Mn and Fe accumulation in welders, traditional and fine motor tasks failed to show significant deficits in welders. We postulated that traditional and fine motor tasks may have inadequate sensitivity for detecting subtle, but functionally important, changes in our welders who have relatively lower levels of exposure. Thus, we have begun to quantify indices of multi-finger synergy, a recent theory-based method that quantifies stability of hand motor function. Another unexpected finding was that neither measure of Mn exposure (i.e., R1 nor PI) correlated with the results of NPTs in our welders, also contrary to our original hypotheses. We postulated that the lack of brain Mn-NPT correlations may be due, at least in part, to the transient nature of Mn accumulation that does not necessarily reflect long-term, cumulative neuropathological changes or consequences, especially when Mn exposure is relatively low. Thus, we implemented diffusion tensor imaging (DTI) to assess brain microstructural changes to capture potential Mn- related neuropathology. Together, these efforts have led to our central hypotheses for the current application: welding exposure, even at low levels, leads to irreversible microstructural changes as indicated by DTI (Aim 1), higher Fe accumulation as indicated by susceptibility mapping (Aim 2), and neurobehavioral consequences that can be captured sensitively by innovative synergy metrics and in- depth neuropsychological testing (Aim 3). The proposed study shall rigorously test the central hypotheses by studying 100 welders (both active and retired) and 60 controls at baseline and at an 18-month follow-up. Lastly, we shall explore that welding exposure, Mn accumulation (R1 & PI), Fe accumulations (R2* & QSM), and microstructural changes (DTI) are on the causal chain leading to synergy and/or neurobehavioral changes, and explore the factors that may modify or interrupt this path (Aim 4).